The overall aim of this application is to better understand the mechanism(s) that lead to diabetes. Of the various common genetic variants associated with type 2 diabetes that in TCF7L2, has the strongest effect on disease predisposition and might provide insight into various diverse mechanisms that drive the progression of prediabetes to diabetes. Indeed, we demonstrated this during the current cycle when we discovered an effect of diabetes-associated variation in TCF7L2 on glucagon suppression. The product of this locus is an important constituent of the wnt-signaling cascade that was originally shown to regulate proglucagon gene expression. In addition, ?-cell function as quantified by the Disposition Index (DI) is also impaired. We propose to examine the temporal relationship of the effects of this locus on ?-cell and on ?-cell function in people with normal glucose tolerance or prediabetes to help examine if impaired glucagon suppression contributes to an increased rate of ?-cell dysfunction or if the two processes develop independently. Since ?-cell dysfunction has previously been overlooked in the pathogenesis of prediabetes, we will harness the Mayo Autopsy resource to examine islet morphology in humans with and without diabetes-associated variation at this locus. Our preliminary data suggests that ?-cell size and glucagon expression is increased in subjects with the T-allele at rs7903146 in the TCF7L2 locus. Finally we have developed a method which enables to measurement of de novo insulin synthesis and secretion in vivo. This will help elucidate the mechanism by which TCF7L2 impairs DI. The proposed experiments will directly address how TCF7L2 alters glucose homeostasis and provide insights into the pathogenesis of prediabetes and progression to diabetes.